U.S. patent number 3,934,013 [Application Number 05/551,811] was granted by the patent office on 1976-01-20 for pharmaceutical composition.
This patent grant is currently assigned to Syntex (U.S.A.) Inc.. Invention is credited to Boyd J. Poulsen.
United States Patent |
3,934,013 |
Poulsen |
January 20, 1976 |
Pharmaceutical composition
Abstract
This invention relates to a topical, anti-inflammatory,
pharmaceutical composition which comprises (a) a pharmaceutically
acceptable solvent, e.g. propylene glycol and water, and (b) at
least two corticosteroids chosen from those represented by formulas
A through K defined hereinafter, each corticosteroid dissolved in
said solvent at a concentration equal to the saturation solubility
for each steroid. Other suitable pharmaceutical formulation
additives may be added to prepare the desired type of formulation,
e.g. cream, ointment, lotion, or gel. The invention includes a
process for preparing the compositions and a method for treating
inflamed skin conditions using the novel compositions.
Inventors: |
Poulsen; Boyd J. (Palo Alto,
CA) |
Assignee: |
Syntex (U.S.A.) Inc. (Palo
Alto, CA)
|
Family
ID: |
24202770 |
Appl.
No.: |
05/551,811 |
Filed: |
February 21, 1975 |
Current U.S.
Class: |
514/170 |
Current CPC
Class: |
A61K
9/0014 (20130101); A61K 31/70 (20130101); A61K
47/00 (20130101); A61P 29/00 (20180101); A61K
38/04 (20130101); A61K 47/10 (20130101); A61K
31/58 (20130101); A61K 31/70 (20130101); A61K
2300/00 (20130101); A61K 38/04 (20130101); A61K
2300/00 (20130101) |
Current International
Class: |
A61K
38/04 (20060101); A61K 47/10 (20060101); A61K
47/00 (20060101); A61K 31/58 (20060101); A61K
031/56 () |
Field of
Search: |
;424/239,240
;260/239.55D |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Roberts; Elbert L.
Attorney, Agent or Firm: Moran; Tom M.
Claims
I claim as my invention:
1. A topical, anti-inflammatory, pharmaceutical composition which
comprises
a. a pharmaceutically acceptable solvent and
b. at least two corticosteroids, each dissolved in said solvent at
a concentration equal to the saturation solubility for each
corticosteroid, said corticosteroids being chosen from the group
represented by the following formulas: ##SPC7##
wherein
in compound (A) R is ##EQU13## in compound (B) R is H, in compound
(C) R is ##EQU14## in compound (D) R is ##EQU15## in compound (E) R
is ##EQU16## in compound (F) R is ##EQU17## ##SPC8##
in compound (G) R.sup.1 is F; X and X.sup.1 both Cl, Z is a double
bond;
in compound (H) R.sup.1 is OH; X and X.sup.1 are both Cl, Z is a
double bond;
in compound (I) R.sup.1 is OH; X is H and X.sup.1 is OH, Z is a
single bond;
in compound (J) R.sup.1 is ##EQU18## X is H, and X.sup.1 is OH, Z
is a double bond; and compound (K) is ##SPC9##
2. The composition of claim 1 wherein said solvent comprises a
mixture of 15%w or more of a glycol and 85%w or less water.
3. The composition of claim 2 wherein said glycol is propylene
glycol.
4. The composition of claim 3 wherein said corticosteroids are
chosen from the group consisting of compounds A,C,D,E, and F.
5. The composition of claim 4 which comprises a mixture of three of
said corticosteroids.
6. A topical, anti-inflammatory, pharmaceutical composition which
comprises
a. a pharmaceutically acceptable solvent;
b. suitable pharmaceutical formulation additives;
c. at least two corticosteroids, each dissolved in said solvent at
a concentration equal to the saturation solubility for each
corticosteroid, said corticosteroids being chosen from the group
consisting of those represented by the following formulas,
##SPC10##
wherein
in compound (A) R is ##EQU19## in compound (B) R is H in compound
(C) R is ##EQU20## in compound (D) R is ##EQU21## in compound (E) R
is ##EQU22## in compound (F) R is ##EQU23## ##SPC11##
in compound (G) R.sup.1 is F; X and X.sup.1 are both Cl; Z is a
double bond
in compound (H) R.sup.1 is OH; X and X.sup.1 are both Cl; Z is a
double bond
in compound (I) R.sup.1 is OH; X is H; and X.sup.1 is OH; Z is a
single bond
in compound (J) R.sup.1 is ##EQU24## X is H; and X.sup.1 is OH; Z
is double bond and compound (K) is ##SPC12##
said corticosteroids being present at a total concentration of
about 0.001% by weight to about 0.5% by weight.
7. The composition of claim 6 wherein said corticosteroids are
present in the relative amounts shown in the following list:
compound A present at 1.00 relative part
compound B present at 22 - 33 relative parts
compound C present at 0.17 - 0.48 relative part
compound D present at 0.14 - 0.38 relative part
compound E present at 0.32 - 2.70 relative parts
compound F present at 0.13 - 0.98 relative part
compound G present at 0.020 - 0.25 relative part
compound H present at 1.50 - 19.05 relative parts
compound I present at 54.50 - 90.48 relative parts
compound J present at 0.25 - 5.00 relative parts
compound K present at 1.60 - 7.40 relative parts
8. The composition of claim 6 wherein said solvent is a mixture
comprising about 15% by weight glycol or more and 85% by weight or
less water.
9. The composition of claim 8 wherein said glycol is propylene
glycol.
10. The composition of claim 9 wherein said group consists of
corticosteroids represented by formulas A,C,D,E,F,G,H,J and K.
11. The composition of claim 10 wherein said group consists of
corticosteroids represented by formulas A,C,D,E and F.
12. The composition of claim 11 wherein 3 corticosteroids are
present in said composition.
13. The composition of claim 8 which comprises
a. about 1.0 to 99.9% by weight of said pharmaceutically acceptable
solvent, wherein said glycol is propylene glycol;
b. about 0.1 to 99% by weight suitable pharmaceutical additives,
and
c. about 0.005 to about 0.20% by weight of said corticosteroid
mixture.
14. The composition of claim 6 which is a cream formulation
comprising
a. about 55 to 99% by weight a solvent comprising (i) 15% by weight
or more of a glycol and (ii) 85% by weight or less water;
b. about 1 to 20% by weight fatty alcohol;
c. about 0 to 10% by weight non-ionic surfactant;
d. about 0 to 10% by weight mineral oil;
e. about 0 to 5% by weight other typical pharmaceutical adjuvants;
and
f. about 0.001 to 0.5% by weight of a mixture of from 2 to 5 of
said corticosteroids.
15. The composition of claim 14 which comprises
a. about 75 to 95% by weight of a solvent comprising (i) about 15
to 60% by weight propylene glycol and (ii) about 40 to 85% by
weight water;
b. about 5 to 10% by weight fatty alcohol;
c. about 0.1 to 5% by weight non-ionic surfactant;
d. about 0 to 8% by weight mineral oil;
e. about 0 to 2% by weight other typical pharmaceutical adjuvants;
and
f. about 0.005 to 0.20% by weight of a mixture of from 2 to 5
corticosteroids chosen from the group represented by formulas A, C,
D, E and F.
16. The composition of claim 15 wherein said mixture of
corticosteroids comprises A, C and D.
17. The composition of claim 15 which includes an effective amount
of an antibiotic.
18. The composition of claim 6 which is an ointment formulation
comprising
a. about 45 to 94% by weight white petrolatum;
b. about 5 to 20% by weight mineral oil;
c. about 1 to 15% by weight pharmaceutically acceptable
solvent;
d. about 0 to 10% by weight pharmaceutically acceptable
surfactant;
e. about 0 to 10% by weight stabilizer;
f. about 0.001 to 0.5% by weight of a mixture of from 2 to 5 of
said corticosteroids.
19. The composition of claim 18 which comprises
a. about 75 to 90% by weight white petrolatum;
b. about 5 to 10% by weight mineral oil;
c. about 2 to 8% by weight propylene glycol;
d. about 0.5 to 5% by weight surfactant;
e. about 0.1 to 2% by weight stabilizer
f. about 0.005 to 0.2% by weight of a mixture of from 2 to 5
corticosteroids chosen from the group consisting of those
represented by formulas A, C, D, E and F.
20. The composition of claim 19 wherein said mixture of
corticosteroids comprises those represented by formulas A, C and
D.
21. The composition of claim 18 which includes an effective amount
of an antibiotic.
22. The composition of claim 6 which is a gel formulation
comprising
a. about 90 to 99.9% by weight of a suitable solvent comprising
about 15 to 90% by weight of a pharmaceutically acceptable glycol
and about 10% to 85% by weight water;
b. about 0.1 to 10% by weight of a suitable gelling agent; and
c. about 0.001 to 0.5% by weight of a mixture of from 2 to 5 of
said corticosteroids.
23. The composition of claim 20 which comprises
a. about 0.5 to 2.0% by weight of carboxypolymethylene;
b. about 98 to 99.50% by weight of a solvent wherein said glycol is
propylene glycol; and
c. about 0.005 to 0.2% by weight of a mixture of from 2 to 5
corticosteroids chosen from the group consisting of those
represented by formulas A, C, D, E and F.
24. A topical, anti-inflammatory, pharmaceutical cream composition
which comprises
0.0082 % by weight fluocinonide;
0.0039 % by weight fluocinolone acetonide-21-propionate;
0.0029 % by weight fluocinolone acetonide-21-cyclopropyl
carboxylate;
4.00 % by weight Cetyl alcohol;
4.00 % by weight Stearyl alcohol;
2.00 % by weight Tween 60;
2.00 % by weight Span 60;
5.75 % by weight mineral oil;
30.00 % by weight propylene glycol; and
enough water to bring the total to 100.00.
25. The cream composition of claim 24 which comprises in addition
0.3500 % by weight neomycin base (as sulfate).
26. The cream composition of claim 24 which comprises in addition
0.2875 % by weight neomycin base (as sulfate), 0.0275 % by weight
gramicidin, and 12.times.10.sup.6 International Units mystatin.
27. A topical, anti-inflammatory pharmaceutical gel composition
which comprises
0.012 % by weight fluocinonide
0.0056 % by weight fluocinolone acetonide 21-propionate;
0.0045 % by weight fluocinolone acetonide 21-cyclopropyl
carboxylate,
0.50 % by weight CARBOPOL; and
enough solvent to bring the total to 100.00, said solvent
comprising about 70 per cent by weight propylene glycol and 30 per
cent by weight water.
28. A topical, anti-inflammatory, pharmaceutical ointment
composition which comprises
0.0112 % by weight fluocinonide;
0.0042 % by weight fluocinolone acetonide-21-acetate;
0.0110 % by weight fluocinolone acetonide-21-cyclopropyl
carboxylate;
8.00 % by weight mineral oil;
8.00 % by weight propylene glycol;
2.00 % by weight Tween 60;
2.00 % by weight Span 60; and
enough white petrolatum to bring the total to 100.00.
29. A process which comprises
dissolving at least two corticosteroids chosen from the group of
corticosteroids represented by the formulas (A) through (K) as
shown below in a suitable pharmaceutical solvent so that each
corticosteroid is present in solution at its saturation solubility
##SPC13##
wherein
in compound (A), R is ##EQU25## In compound (B), R is H, in
compound (C), R is ##EQU26## in compound (D), R is ##EQU27## in
compound (E), R is ##EQU28## in compound (F), R is ##EQU29##
##SPC14##
in compound (G), R.sup.1 is F; X and X.sup.1 both Cl, Z is a double
bond;
in compound (H), R.sup.1 is OH; X and X.sup.1 are both Cl, Z is a
double bond
in compound (I), R.sup.1 is OH; X is H and X.sup.1 is OH, Z is a
single bond;
in compound (J), R.sup.1 is ##EQU30## X is H, and X.sup.1 is OH, Z
is a double bond; and compound (K) is ##SPC15##
and
mixing said resulting solution with an effective amount of suitable
pharmaceutical formulation additives to form a topical,
anti-inflammatory, pharmaceutical composition which comprises about
0.001% by weight to about 0.5% by weight of said
corticosteroids.
30. The process of claim 29 wherein said solvent is a mixture
comprising about 15% by weight glycol or more and 85% by weight or
less water.
31. The process of claim 30 wherein said glycol is propylene
glycol.
32. The process of claim 31 wherein said group consists of
corticosteroids represented by formulas A,C,D,E,F,G,H, J and K.
33. The process of claim 32 wherein said group consists of
corticosteroids represented by formulas A,C,D,E and F.
34. The process of claim 33 wherein 3 corticosteroids are present
in said composition.
35. The process of claim 29 wherein said solvent is a mixture of
about 15% by weight or more propylene glycol and 85% by weight or
less water and the resulting topical, anti-inflammatory,
pharmaceutical composition comprises
a. about 1.0 to 99.9% by weight of said pharmaceutically acceptable
solvent,
b. about 0.1 to 99% by weight suitable pharmaceutical additives,
and
c. about 0.005 to about 0.20% by weight of said corticosteroid
mixture.
36. The process of claim 29 wherein said pharmaceutical composition
is a cream formulation which comprises
a. about 55 to 99% by weight solvent comprising
i. 15% by weight or more of a glycol and
ii. 85% by weight or less water, and
b. suitable pharmaceutical additives comprising
i. about 1 to 20% by weight fatty alcohol;
ii. about 0 to 10% by weight non-ionic surfactant;
iii. about 0 to 10% by weight mineral oil;
iv. about 0 to 5% by weight typical pharmaceutical adjuvants.
37. The process of claim 29 wherein said pharmaceutical composition
is an ointment formulation which comprises
a. about 1 to 15% by weight of said pharmaceutically suitable
solvent which is a glycol;
b. suitable pharmaceutical additives comprising
i. about 45 to 94% by weight white petrolatum;
ii. about 5 to 20% by weight mineral oil;
iii. about 0 to 10% by weight pharmaceutically acceptable
surfactant; and
iv. about 0 to 10% by weight stabilizer.
38. The process of claim 29 wherein said pharmaceutical composition
is a gel formulation comprising
a. about 90 to 99.9% by weight of a suitable solvent comprising
about 15 to 90% by weight of a pharmaceutically acceptable glycol
and about 10% to 85% by water;
b. about 0.1 to 10% by weight of a suitable pharmaceutical
formulation additive which is a gelling agent; and
c. about 0.001 to 0.5% by weight of a mixture of from 2 to 5 of
said corticosteroids.
39. A process of treating inflammatory conditions which comprises
topically administering an effective amount of a composition which
comprises
a. a pharmaceutically acceptable solvent;
b. suitable pharmaceutical formulation additives;
c. at least two corticosteroids, each dissolved in said solvent at
a concentration equal to the saturation solubility for each
corticosteroid, said corticosteroids being chosen from the group
consisting of those represented by the following formulas
##SPC16##
wherein
in compound (A) R is ##EQU31## in compound (B) R is H in compound
(C) R is ##EQU32## in compound (D) R is ##EQU33## in compound (E) R
is ##EQU34## in compound (F) R is ##EQU35## ##SPC17##
in compound (G) R.sup.1 is F, X.sup.1 are both Cl, Z is a double
bond;
in compound (H) R.sup.1 is OH, X and X.sup.1 are both Cl, Z is a
double bond;
in compound (I) R.sup.1 is OH, X is H; and X.sup.1 is OH, Z is a
single bond;
in compound (J) R.sup.1 is ##EQU36## X is H, X.sup.1 is OH, Z is a
double bond; and compound (K) is ##SPC18##
said corticosteroids being present at a total concentration of
about 0.001% by weight to about 0.5% by weight.
40. The process of claim 39 wherein said solvent is a mixture
comprising about 15% by weight glycol or more and 85% by weight or
less water.
41. The process of claim 40 wherein said glycol is propylene
glycol.
42. The process of claim 41 wherein said group consists of
corticosteroids represented by formulas A, C, D, E, F, G, H, J and
K.
43. The process of claim 42 wherein said group consists of
corticosteroids represented by formulas A, C, D, E and F.
44. The process of claim 43 wherein 3 corticosteroids are present
in said composition.
45. The process of claim 39 wherein said solvent is a mixture of
about 15% by weight or more propylene glycol and 85% by weight or
less water and the resulting topical, anti-inflammatory,
pharmaceutical composition comprises
a. about 1.0 to 99.9% by weight of said pharmaceutically acceptable
solvent,
b. about 0.1 to 99% by weight suitable pharmaceutical additives,
and
c. about 0.005 to about 0.20% by weight of said corticosteroid
mixture.
46. The process of claim 39 wherein said composition is a cream
formulation which comprises
a. about 55 to 99% by weight solvent comprising
i. 15% by weight or more of a glycol and
ii. 85% by weight or less water, and
b. suitable pharmaceutical additives comprising
i. about 1 to 20% by weight fatty alcohol;
ii. about 0 to 10% by weight non-ionic surfactant;
iii. about 0 to 10% by weight mineral oil;
iv. about 0 to 5% by weight typical pharmaceutical adjuvants.
47. The process of claim 39 wherein said pharmaceutical composition
is an ointment formulation which comprises
a. about 1 to 15% by weight of said pharmaceutically suitable
solvent which is a glycol;
b. suitable pharmaceutical additives comprising
i. about 45 to 94% by weight white petrolatum;
ii. about 5 to 20% by weight mineral oil;
iii. about 0 to 10% by weight pharmaceutically acceptable
surfactant; and
iv. about 0 to 10% by weight stabilizer.
48. The process of claim 29 wherein said pharmaceutical composition
is a gel formulation comprising
a. about 90 to 99.9% by weight of a suitable solvent comprising
about 15 to 90% by weight of a pharmaceutically acceptable glycol
and about 10% to 85% by water;
b. about 0.1 to 10% by weight of a suitable pharmaceutical
formulation additive which is a gelling agent; and
c. about 0.001 to 0.5% by weight of a mixture of from 2 to 5 of
said corticosteroids.
49. The composition of claim 6 which comprises
a. about 1 to 10% by weight of a suitable pharmaceutical
solvent;
b. about 1 to 10% by weight propylene carbonate;
c. about 1 to 10% by weight of a suitable pharmaceutical
surfactant;
d. about 70 to 97% by weight white petrolatum; and
e. about 0.001 to 0.5% by weight of said corticosteroids.
50. The composition of claim 49 which comprises
a. about 2 to 6% by weight of a glycol solvent;
b. about 1 to 4% by weight propylene carbonate;
c. about 1 to 5% by weight of said surfactant;
d. about 85 to 95% by weight white petrolatum; and
e. about 0.005 to 0.2% by weight of a mixture of from 2 to 5
corticosteroids chosen from the group consisting of those
represented by formulas A, C, D, E, and F.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to topical anti-inflammatory pharmaceutical
compositions which are useful for treating diseases of the skin,
particularly inflammatory manifestations of
corticosteroid-responsive dermatoses. The composition comprises a
suitable pharmaceutical solvent and dissolved therein at least two
corticosteroid compounds defined hereinafter, each corticosteroid
being present at a specific amount relative to the others. Further,
the new compositions of this invention provide improvement in the
treatment of inflamed condition of the skin. A new method for the
preparation of the compositions of this invention is also
disclosed.
2. Prior Art
The direct application of drugs to the skin surface has been used
since antiquity to treat diseases of the skin. In general, the skin
is an effective barrier to the passage of externally applied agents
and most chemical substances penetrate intact skin poorly. Since
the pharmacological effect of a drug is dependent on achieving a
certain threshold concentration in the viable tissues of the skin,
effective therapy requires sufficient percutaneous absorption of
the drug to achieve the required tissue concentration levels.
The primary barrier to the precutaneous absorption of drugs has
been identified as the stratum corneum, the layer of stratified and
keratinized dead cells at the skin surface. The ability of chemical
agents or drugs to diffuse across the stratum corneum into the
deeper tissues is directly related to the physical chemical
properties of the drugs. It is known that certain low molecular
weight organic solvents such as acetone, chloroform, and dimethyl
sulfoxide penetrate the human skin more readily (i.e. at a faster
rate) than most drugs, particularly substances of high molecular
weight such as corticosteroids. For such compounds, the therapeutic
effectiveness is greatly dependent on the rate of diffusion from
the topical vehicle (the base) into the skin, i.e. the penetration
rate. Increasing the rate of diffusion is an important mechanism
for improving therapeutic effectiveness of many topically applied
drugs.
The most obvious and commonly used method for increasing the
penetration rate of a topically applied drug is to increase its
concentration in the vehicle. There are limitations to this
approach that bear directly upon the utility of the present
invention. For the greatest proportion of skin diseases requiring
topical therapy, the skin is the principal barrier to drug
absorption and drug absorption proceeds by the process of passive
diffusion. Thus only the concentration of drug actually in solution
in the vehicle directly affects the drug penetration rate. For a
given vehicle and drug, increasing the drug concentration
appreciably beyond the saturation concentration in the vehicle will
have only a marginal effect on the rate of percutaneous absorption.
Thus in a suspension, i.e. a drug formulation wherein a substantial
majority of the drug is present in the pure, undissolved state,
very little, if any, increase in absorption rate will be seen from
adding more excess drug so long as the skin acts as the primary
barrier to drug absorption.
Marcus et al. [J. Pharm. Sci., 54, 495-6 (1965)] have described
improved in vitro release into water for mixtures of two steroids.
In their report data are present for two different mixtures:
dexamethasone plus prednisolone and dexamethasone plus
betamethasone. The systems described by Marcus et al. differ
completely from those described in the present invention. In the
Marcus et al. article an experimental situation is described where
release from the vehicle is the rate-limiting step in diffusion
instead of diffusion through the skin barrier -- the case which
normally prevails in the precutaneous absorption of drugs. Marcus
et al. describe formulations where the drug is present primarily as
suspended solid particles instead of the solubilized systems
described in this invention. They also state that rlease is
independent of the nature of the vehicle whereas in the present
invention vehicle composition must be carefully adjusted depending
on the nature and total concentration of the steroid mixture
employed. The present invention also requires careful selection of
compounds used in a specific vehicle and adjustment of the relative
amounts of each steroid according to their saturation solubility.
Thus, although an increase in the rate of release of suspended drug
into water may be seen, a corresponding rate of penetration of the
stratum corneum is not seen using suspension systems because the
diffusional resistance of the skin may be any where from 1000 of
several million times greater than that offered by water or
ointment based vehicles. (See for example Scheuplun, R. J.,
Molecular Structure and Diffusional Processes Across Intact
Epidermis, Final Comprehensive Report No. 7, Springfield U.S. Dept.
of Commerce, 1966 and Higuchi, W. I., J. Pharm. Sci., Vol 5, pp.
802-4, 1962. )
The limitations inherent in systems where the drug (or drugs) are
presented in the form of suspended material in a vehicle has been
analyzed by Katz and Poulsen ("Absorption of Drugs Through The
Skin" in Experimental Pharmacology Ed. B. B. Brodie, pub. Springer
Verlag 1971) and by Poulsen ("Design of Topical Drug Product:
Biopharmaceutics" in Drug Design Vol. 4 Ed. E. J. Ariens, pub.
Academic Presd, 1974).
It is known that pregnenolone hemiesters and their salts may be
applied topically as a mixture for the treatment of alleviating
allergic, pruritic and inflammatory skin conditions. See for
example U.S. Pat. No. 3,197,367 issued July 27, 1965 to Panzarella.
Not only is this class of compounds completely different from the
corticosteroids employed in the composition of this invention, but
also a greater percentage of the active ingredients is required for
therapeutic activity. It is also mentioned in U.S. Pat. No.
3,743,741 issued July 3, 1973 to Laurent et al. that mixtures of
two 9-chloro substituted prednisolones may be used as an ointment.
No particular advantage of the mixture over either one alone at an
equivalent concentration is discussed, however. The compounds of
U.S. Pat. No. 3,743,741 are entirely different than the compounds
employed in this invention. Mixtures of 1-dehydrocortisone,
1-dehydrocortisol, and the corresponding 9.alpha.-chloro- or
fluoro-derivatives are disclosed in U.S. Pat. No. 3,134,718 to
Nobile. The compounds of the Nobile patent are entirely different
than the compounds useful in the compositions of this invention and
the combination of Nobile is not shown to have any particular
advantage over a composition having an equivalent concentration of
any of the drugs alone. Another mixture of steroids, fluocortolone
and fluocortolone caproate, has been marketed by Schering Ag as
Ultralan. These compounds and the ratios at which they are employed
are entirely different than the mixture of this invention.
I have now discovered that a particular group of corticosteroids
when applied as mixtures in a topical vehicle show an increased
rate of penetration of the stratum corneum which is greater than
any one of the corticosteroids alone at an equivalent
concentration. Surprisingly, the total rate of corticosteroid
penetration is substantially additive, a result heretofore not
shown in the prior art for pharmaceutical solutions. The new
composition of this invention, which is in essence a solution,
exhibits a greater penetration rate than does a suspension system
of similar composition. Thus, not only does the composition of this
invention offer the advantage of greater activity, but also because
it is in essence a solution of the drug in an acceptable
pharmaceutical solvent, the composition is generally a more
homogeneous mixture which is not plagued by crystallization
problems as suspensions often are. It has also been found that the
combination composition of this invention can be adjusted so that
the total concentration of the individual drugs used is small
enough to reduce the potential for side effects of any of the
individual drugs used at a concentration equivalent to the total
concentration of each corticosteroid used in the composition of
this invention. This results, of course, in a safer drug
composition.
SUMMARY OF THE INVENTION
In its broadest aspect this invention is a topical,
antiinflammatory, pharmaceutical composition which comprises
a. a pharmaceutically acceptable solvent and
b. at least two corticosteroids, each dissolved in the solvent at a
concentration equal to the saturation solubility for each
corticosteroid, the corticosteroids being chosen from the group
represented by the following formulas: ##SPC1##
wherein
in compound (A) R is ##EQU1## in compound (B) R is H, in compound
(C) R is ##EQU2## in compound (D) R is ##EQU3## in compound (E) R
is ##EQU4## in compound (F) R is ##EQU5## ##SPC2## in compound (G)
R.sup.1 is F; X and X.sup.1 both Cl, Z is a double bond,
in compound (H) R.sup.1 is OH; X and X.sup.1 are both Cl, Z is a
double bond,
in compound (I) R.sup.1 is OH; X is H and X.sup.1 is OH, Z is a
single bond,
in compound (J) R.sup.1 is ##EQU6## X is H, and X.sup.1 is OH, Z is
a double bond and compound (K) is ##SPC3##
Particularly effective as the solvent in the composition of this
invention is a mixture of about 15% by weight or more of a glycol,
preferably propylene glycol, and about 85% by weight or less water.
Preferably the corticosteroid mixture comprises 3 compounds chosen
from the group A,C,D,E, and F, more specifically compounds A,C and
D. Other preferred aspects of the composition of this invention
will be discussed hereinafter.
Another aspect of this invention is a process of treating
inflammatory conditions which process comprises topically
administering an effective amount of the composition of this
invention.
Still another aspect of this invention is a process for preparing
the composition of this invention which process comprises
dissolving at least two corticosteroids chosen from the group
consisting of those represented by the formulas (A) through (K)
discussed hereinafter so that each corticosteroid is dissolved at
its saturation solubility concentration,
mixing the resulting solution with an effective amount of suitable
pharmaceutical formulation additives to prepare a topical,
anti-inflammatory, pharmaceutical composition which comprises about
0.001%w to about 0.5%w of said corticosteroids.
PREFERRED EMBODIMENTS
The essence of the invention is utilizing a mixture of active
ingredients, steroids, hereinafter defined, each of which has a
chemical structure differing from the others but each having
similar therapeutic (anti-inflammatory) activities, the steroids
being present in solution at specific ratios relative to each
other, the ratios being governed at least in part by the
concentration of each steroid, which is equal to its saturation
solubility in the solvents employed. The mixture is dissolved in a
suitable pharmaceutical solvent which may be substantially
anhydrous or may be mixed with water, depending on what type of
formulation will be used for topical application, i.e. cream,
ointment, lotion, gel, or the like. Generally the steroids are more
soluble in anhydrous solvents such as a glycol than in a
solvent/water mixture and the exact ratio of steroids will be
affected by the presence of water, each steroid having its own
independent solubility characteristics in each solvent system being
employed. The ratios given for compounds found to be useful in this
invention [(A) through (K), below] are set by arbitrarily giving
compound (A) the value of 1.00 and relating the relative amounts of
the other steroids present to compound (A). Each has then a ratio
range relative to A and to each other steroid. By employing the
steroids in a particular formulation at these ratios, not only is
the maximum activity for each compound obtained but also the total
activity is greater than any one of the compounds alone at an
equivalent concentration.
The specific multisteroid composition of this invention offers
certain advantages over comparable single steroid compositions
known in the art. (1) The activity, as measured by the rate of
total steroid penetration across the stratum corneum is greater for
the composition of this invention than for a single steroid
composition of equivalent concentration. (2) Because of (1) there
appears an enhanced clinical response to the composition of this
invention compared to a comparable known formulation having an
equivalent concentration of one steroid alone. (3) Reduced doses of
the individual steroids may be used due to superior total
penetration. (4) The potential for side effects in the target
species is reduced because of the lower total dose of drug
required. (5) Further, because of flexibility in formulation,
topical, anti-inflammatory compositions having low glycol solvent
contents to reduce the chance of irritation in users who have an
adverse reaction to glycols, such as propylene glycol.
Broadly, the topical, anti-inflammatory, pharmaceutical composition
of this invention comprises
a. a pharmaceutically acceptable solvent and
b. at least two corticosteroids, each dissolved in the solvent at a
concentration equal to the saturation solubility for each compound.
The corticosteroids are chosen from the group represented by the
formulas (A) through (K) presented hereinafter, the total
concentration of corticosteroids dissolved being less than about
0.5% by weight of the final pharmaceutical composition and the
corticosteroids being present in amounts relative to each other
such that the activity, as measured by the total steroid
penetration rate across a membrane, such as the stratum corneum, is
greater for the mixture than for any of the corticosteroids alone
at an equivalent total amount.
A pharmaceutically acceptable solvent is one which (i) is
substantially non-toxic and non-irritating under the conditions
used, (ii) will dissolve a sufficient amount of the drugs used to
give the desired effect, and (iii) may be readily formulated into
any of the classical drug formulations such as creams, ointments,
lotions, or gels. Particularly suitable solvents include water,
glycerin, propylene carbonate, and glycols such as a 1,2-propylene
diol (i.e. propylene glycol), 1,3-propylene diol or mixtures
thereof; polyethylene glycol having molecular weight of from 100 to
800; dipropylene glycol; etc.; and mixtures of the aforementioned
with each other. Preferably the pharmaceutically acceptable solvent
will be a glycol, particularly propylene glycol (PG), either alone
or admixed with water. A particularly preferred solvent comprises
15% by weight or more of a suitable glycol, preferably PG, and 85%
by weight or less water.
The topical, anti-inflammatory pharmaceutical composition of this
invention requires that at least two of the corticosteroid,
compounds, and preferably no more than 5, be present in solution,
the compounds being chosen from those represented by the following
structures (A) through (K) in relative amounts shown adjacent the
respective structures; each of the drugs being present at
concentration in the pharmaceutically acceptable solvent equal to
that drug's saturation solubility in the solvent. Preferably the
solvent comprises at least 15% by weight (%w) propylene glycol or
more and 85% w water or less. The compounds are represented by:
##SPC4##
wherein for
(A) R is ##EQU7## present at 1.00 relative part; (B) R is --H
present at 22-33 relative parts;
(C) R is ##EQU8## present at 0.17- 0.48 relative part; (D) R is
##EQU9## present at 0.14- 0.38 relative part; (E) R is ##EQU10##
present at 0.32-2.70 relative parts; and (F) R is ##EQU11## present
at 0.13-0.98 relative part; ##SPC5##
wherein for
(G) Z is a double bond, R.sub.1 is F and X and X.sub.1 and Cl:
present at 0.02-0.25 relative part;
(H) Z is a double bond, R.sub.1 is OH and X and X.sub.1 are Cl:
present at 1.50-19.05 relative parts; and
(I) Z is a single bond; R.sub.1 is OH, X is H, X.sub.1 is OH:
present at 54.50-90.48 relative parts;
(J) Z is a double bond, R.sub.1 is ##EQU12## X is H, and X.sub.1 is
OH present at 0.25-5.00 relative parts; (K) is ##SPC6##
present at 1.60-7.40 relative parts.
Following is the list of compounds A through K with their
corresponding common names:
(A) Fluocinonide
(B) Fluocinolone acetonide
(C) Fluocinolone acetonide 21-propionate
(D) Fluocinolone acetonide 21-cyclopropyl carboxylate
(E) Fluocinolone acetonide 21-cyclobutyl carboxylate
(F) Fluocinolone acetonide 21-valerate
(G) 6.alpha., 21-difluoro-9.alpha., 11.beta.-dichloro-16.alpha.,
17.alpha.-isopropylidenedioxy-1,4-pregnadiene-3, 20-dione
(H) Fluclorolone acetonide
(I) Flurandrenolide
(6.alpha.-fluoro-16.alpha.-hydroxyprednisolone-16,
17-acetonide)
(J) Flunisolide-21-acetate
(K) Flumethasone-21-acetate
Compounds A through F, I and J may be prepared by methods known in
the art, particularly those disclosed in U.S. Pat. No. 3,126,375 to
Ringold, et al. and U.S. Pat. No. 3,014,938 to Mills et al.
Compound G may be prepared as disclosed in U.S. Pat. No. 3,409,613
to Fried; compound H by the methods disclosed in U.S. Pat. No.
3,201,391 to Bowers; and compound K by methods shown in J. Am.
Chem. Soc. 81, 3156 (1959). As much of these patents or journals as
is pertinent is incorporated herein by reference.
In designing the mixtures of this composition it is preferred that
the mixture include those compounds from those represented by A
through K which have about the same level of solubility. Thus in a
formulation which is substantially anhydrous ("substantially
anhydrous" meaning less than about 3%w water) employing a
pharmaceutically acceptable solvent such as propylene glycol, the
following mixtures and ratios are exemplary as effective ratios but
are not to be construed as limiting:
compounds A/C/D/E/F 1.00/.42/.38/2.71/.98 compounds D/E/F
.38/2.71/.98 compounds B/I 32.10/54.50 compounds F/H/K
.98/1.50/1.60 compounds C/D/G/J .42/.38/.25/.25 compounds A/C/D
1.00/.42/.38 compounds A/F/H/K 1.00/.98/1.50/1.60
On the other hand in a formulation wherein the solvent is
substantially water, i.e. about 96%w or more of water with 5%w or
less PG the following mixtures and ratios are exemplary, but are
not to be construed as limiting:
compounds A/C/D/E 1.00/.31/.24/.56 compounds F/G .17/.02 compounds
B/H/I 33.30/19.05/90.48 compounds H/K 19.05/7.4 compounds B/I
33.3/90.48 compounds C/D/E .31/.24/.56 compounds A/C/D
1.00/.31/.24
In the formulation wherein the solvent is a mixture of about 60%w
PG and 40%w water, the following mixtures and ratios are exemplary,
but again are not to be construed as limiting:
compounds A/C/D/E/F 1.00/.47/.32/1.47/.39 compounds C/D/F
.47/.32/.39 compounds A/E 1.00/1.47 compounds A/C/D
1.00/.47/.32
The enhanced penetration effects of these combinations may be seen
over a wide range of concentrations as long as the drugs are kept
at their saturation solubility. Relative to the solvent, the
mixture of corticosteroids is dissolved at levels which depend on
the particular solvent and may vary from about 1.0 microgram
(mg)/milliliter (ml) of solvent to about 10 milligrams
(mg)/milliliter of solvent to obtain the increased penetration
rate. The mixture of corticosteroids is first dissolved in the
solvent then formulated into a composition which may be applied
topically as any suitable classical formulation as described in the
United States Pharmacopoeia XVII, for example as a (1) cream, (2)
ointment, (3) lotion, or (4) gel, the total corticosteroid
concentration in the final formulation being a therapeutically
effective amount which will generally be between about 0.001 and
0.5%w, preferably less than about 0.2%w but more than about
0.005%w.
It is important to realize that for this composition the
corticosteroids are dissolved in the solvent and are at their
saturation solubility concentrations, i.e, the maximum amount
dissolved in the solvent at a given temperature. Although some of
the corticosteroids may be present outside of solution, the
presence of excess steroid in the pure form does not significantly
enhance the rate of penetration of the composition. In some cases,
particularly if the total drug concentration is low, it may be
considered advisable for some excess, undissolved drug to be
present in order to maintain maximum thermodynamic activity of each
drug entity, i.e. to sustain the concentration of each drug at its
saturation solubility concentration. However, even though there may
be some drug present which is undissolved, the majority of each of
the drugs present is in solution.
The group of corticosteroids which are eminently suitable for use
in the composition of this invention are those which exhibit about
the same level of solubility in the solvent employed. Such a group
comprises a mixture of at least 2 of the compounds represented by
the formulas A, C--H, J, and K.
Particularly valuable in this regard are mixtures of
corticosteroids chosen from the fluocinolone acetonide esters
represented by formulas A,C,D,E and F above.
Preferably, this invention is a topical, anti-inflammatory,
pharmaceutical composition which comprises
a. a suitable pharmaceutical solvent, preferably about 1 to 99.9%w
of a mixture of about 15%w or more propylene glycol and 85%w or
less water,
b. suitable pharmaceutical formulation additives preferably about
0.1 to 99%w; and
c. dissolved in the solvent, a mixture of at least 2
corticosteroids chosen from the group consisting of compounds
represented by formulas A through K above, preferably formulas
A,C,D,E and F, above, each steroid being present at the relative
amounts set forth hereinbefore. The total concentration of the
steroids in the pharmaceutical composition is 0.001 and 0.5%w,
preferably 0.005 and 0.20%w, and even more preferably between about
0.01 to about 0.015%w.
A discussion of representative formulations which utilizes the
above solution of corticosteroids and suitable pharmaceutical
formulation additives follows below. It is to be understood that in
the following discussion "active ingredients" refers to the total
amount of the mixture of at least two of compounds A through K
present in the particular formulation. Preferably the mixture will
contain no more than 5 compounds in solution at the ratios set
forth above, and even more preferably will consist of 3 of the
compounds, particularly 3 chosen from compounds A,C,D,E, and F.
1. Cream
The topical, anti-inflammatory corticosteroid mixture may be
prepared and applied in a cream base, i.e. a semi-solid emulsion of
oil in water or water in oil. By definition an emulsion is a two
phase system with one liquid (e.g. fats or oils) being dispersed as
small globules in the other substance (e.g. the glycol/water
solvent phase employed as the primary solvent for the
corticosteroid mixture). Typically the cream formulation may
contain (other than the solution of corticosteroids) fatty
alcohols, surfactants, mineral oil or petrolatum and other typical
pharmaceutical adjuvants such as antioxidants, antiseptics, or
compatible adjuvants.
The following cream base formulation is representative of the
compositions of this invention:
Cream Base Operative Preferred Ingredient range(%w) range(%w)
______________________________________ Water/glycol mixture 55 - 99
75 - 95 (15% or more glycol) Fatty alcohol 1 - 20 5 - 10 Non-ionic
Surfactant 0 - 10 0.1 - 5 Mineral oil 0 - 10 0 - 8 Typical
pharmaceutical adjuvants 0 - 5 0 - 2 *Active Ingredients 0.001 -
0.5 0.005 - 0.20 ______________________________________
In general the fatty alcohol ingredient in the cream composition
can be any fatty alcohol having from 16 to 24 carbons or mixtures
thereof and is preferably a saturated, monohydric primary alcohol.
Suitable fatty alcohols include cetyl alcohol, stearyl alcohol,
behenyl alcohol and the like. Vehicles having excellent properties
are prepared using stearyl alcohol or mixtures of cetyl and stearyl
alcohol as the fatty alcohol component.
The concentration of the fatty alcohol ingredients may vary between
about 1 to about 20 percent by weight(%w) of the final, formulated
composition. Preferably the fatty alcohol will be present in
amounts of about 5 to 10%w.
The cream formulation useful to apply the steroid combination of
this invention usually will also contain an effective amount of a
surfactant. An effective amount is enough to assist in maintaining
homogeneity of the vehicle and preventing exudation or bleeding of
the more liquid components of the vehicle such as the glycol
solvent upon prolonged storage at elevated temperatures. Thus, the
vehicle contains a quantity of the surfactant sufficient to
prohibit visible exudation of the more liquid components from the
vehicle after storage at 45.degree. for 48 hours. In some instances
the amount of surfactant required may be small. No more of the
surfactant is used than is needed to prevent this exudation. Excess
quantities are undesirable because other ingredients and their
functions are needlessly diluted. If the surfactant concentration
is not carefully balanced with the other components, stability of
the medicant vehicle after one or more repeated cycles of
solidification (by cooling) in liquification (by heating), that is
the freeze/thaw ability is impaired. Thus, an effective amount of
surfactant will be within the range of from 0 to 10%w of the final,
formulated composition, preferably about 0.1 to 5%w will be
used.
The surfactant may be anionic, cationic, or nonionic, preferably
nonionic. Suitable surfactants include saturated fatty acids having
from 16 to 24 carbons such as stearic acid, palmitic acid, and
behenic acid; fatty amides such as oleamide, palmitamide,
stearamide, and behenamide; and esters of fatty acids having from
16 to 24 carbons such as sorbitan monostearate, polyethylene glycol
monostearate, propylene glycol monostearate, and the corresponding
monoesters of other fatty acids such as oleic acids and palmitic
acids. Best results are achieved particularly with the esters if
the fatty group of the coupling agent and fatty alcohol is the same
or approximately the same number of carbons. It is essential that
the fatty acids be saturated and the fatty acids or amides by
substantially free from irritating amounts of acids or amides
having fewer than 16 carbons.
Particularly valuable as surfactants are the nonionic surfactants
referred to as Span and Tween. The Span type materials are partial
esters of common fatty acids (lauric, palmitic, stearic, and oleic)
and hexitol anhydrides (hexitans and hexides), derived from
sorbitol. The Tween Type materials are derived from the Span
products by adding polyoxyethylene chains to the nonesterified
hydroxyls. Particularly valuable are Span 60, Span 80, and Tween 60
(Available through Atlas Chemical Co.).
A further component of a typical oil/water emulsion cream base is
an effective amount of mineral oil, also referred to as mineral
petrolatum, i.e. about 0 to 10%w, preferably about 1 to 8%w.
The cream will also include a pharmaceutically acceptable glycol
solvent such as discussed above. preferably this glycol solvent
will be a propylene glycol (PG)/water mixture which is 15%w PG or
more, even more preferably about 30% PG but no more than 60%w PG,
the mixture being present at 55-99%w, preferably 70-95%w of the
total cream base formulation. The glycol solvent and the fatty
alcohol ingredients are the principal components in the preferred
composition of the invention, the glycol solvent being the primary
solvent for the corticosteroids used in the formulation although
other adjuvants present such as the surfactants may also contribute
significantly to the drug solubility. The fluidity of the
composition increases with increased concentrations of the glycol
solvent, while the fatty alcohol forms a protective, lubricant and
occlusive film.
Other typical pharmaceutical adjuvants may be included as well; for
example, antiseptics such as thimerosal, a pharmaceutically
acceptable antioxidant such as citric acid; and other additives
conventionally used to improve consistency, homogeneity,
spreadability, texture, and appearance of the vehicle or it's
residual film. The latter can be used to give a residual film
varying degrees of continuity, flexibility, adhesion, occlusion,
water repellancy, washability and the like. Examples of typical
adjuvants include surfactants such as natural gums including agar,
acacia gum, guar gum, tragacanth, and the like; cellulose
derivatives including cellulose ethers such as methyl cellulose,
ethyl cellulose, carboxymethyl cellulose, and the like; starch and
starch derivatives, and water soluble vinyl polymers such as
polyvinylpyrrolidone, polyvinyl alcohol, vinylpyrrolidonevinyl
alcohol copolymers, and the like. Nonessential ingredients may be
present at levels that vary from 0 to 5%w, but preferably less than
about 1% will be present.
2. Ointment
The topical, anti-inflammatory corticosteroid mixtures of this
invention may also be applied as an ointment, preferably a
classical ointment. Generally, a "classical" ointment is a
semi-solid anhydrous composition which may contain mineral oil,
white petrolatum, a suitable solvent such as the glycol solvents
recited hereinbefore (including propylene carbonate), and other
pharmaceutically acceptable additives such as surfactants, e.g.
Span, Tween, or wool fat (lanolin), stabilizers such as
antioxidants (e.g. citric acid), and other adjuvants as mentioned
above. Following is a preferred, classical ointment base
formulation suitable for applying the topical anti-inflammatory
corticosteroid mixture of this invention:
Classical Ointment Base Operable Preferred Ingredient range(%w)
range(%w) ______________________________________ White petrolatum
45 - 94 75 - 90% Mineral oil 5 - 20 5 - 10% Glycol solvent 1 - 15 2
- 8% Surfactant 0 - 10 0.5 - 5% Stabilizer 0 - 10 0.1 - 2% Active
Ingredients 0.001 - 0.5 0.005 - 0.2
______________________________________
Other suitable ointment base formulations which contain propylene
carbonate are described in a co-pending U.S. patent applications
Ser. No. 85,246, filed Oct. 29, 1970 by Shastri et al. entitled
"Propylene Carbonate Ointment Vehicle" and Ser. No. 201,997, filed
Nov. 24, 1971 by Chang et al. entitled "Fatty Alcohol-Propylene
Carbonate-Glycol Solvent Cream Vehicle." As much of those
applications as is pertinent is incorporated herein by reference.
Following is an ointment base formulation containing propylene
carbonate found to be particularly effective for the compositions
of this invention:
Propylene Carbonate Ointment Base Operable Preferred Ingredient
range(%w) range(%w) ______________________________________ Active
Ingredients 0.001 - 0.5 0.005 - 0.2 Propylene Carbonate 1 - 10 1 -
4 Solvent 1 - 10 2 - 6 Surfactant 1 - 10 1 - 5 White Petrolatum 70
- 97 85 - 96 ______________________________________
The surfactant may be any suitable surfactant discussed
hereinbefore while the solvent is preferably a compatible glycol
solvent as discussed previously.
A suitable "non-classical" anhydrous, water washable "ointment
type" base is described in U.S. Pat. No. 3,592,930 to Katz and
Neiman, and as much of that disclosure as is pertinent is
incorporated herein by reference. A composition of this invention
utilizing such a base is as follows:
Water-Soluble Ointment Base Operable Preferred Ingredient range(%w)
range(%w) ______________________________________ Glycol solvent 45
- 85 55 - 80 Fatty alcohol 15 - 45 20 - 35 Compatible plasticizer 0
- 15 2 - 10 Compatible coupling Agent 0 - 15 1 - 5 Penetrant 0 - 20
0 - 10 Active Ingredients 0.001 - 0.5 0.005 - 0.20
______________________________________
The fatty alcohols which are suitable have been previously
disclosed above in this specification and in U.S. 3,592,930. As
much of those disclosures as is pertinent is incorporated herein by
reference. Effective amounts are set forth in the table immediately
above.
The glycol solvent has been described hereinbefore and is
preferably propylene glycol alone.
The composition can also contain an effective amount of a
compatible plasticizer such as polyethylene glycol having a
molecular weight of from above 800 to 20,000, 1,2,6-hexanetriol,
sorbitol, glycerol, and the like. The plasticizer maintains
homogeneity in the fatty alcohol-glycol solvent mixture at ambient
temperatures, that is, temperatures at which the fatty alcohol is
naturally a solid. This component also improves the plasticity and
uniformity of medicant mixtures with the vehicle and provides to
the vehicle smoothness and a more pleasing "feel," hence the
vehicle containing the plasticizer is more aesthetically
acceptable.
The term "compatible" is defined herein to indicate a component
which will not cause separation (loss of homogeneity) of the other
components, that is, the fatty alcohol and glycol solvent at
temperatures up to 45.degree.C.
The plasticizer concentration can be within the range of from 0 to
15 percent. Concentrations above 15 percent may provide a
composition which has a consistency unsuitable for normal
applications or cause instability of the vehicle mixture and some
separation of the components. In general, the particular
plasticizer concentration necessary to provide a desired
consistency, degree of smoothness and plasticity will vary with the
choice of the fatty alcohol component, the choice of glycol
solvent, and the ratio of these components in the vehicle.
The particular concentration of plasticizer which will provide the
most stable composition will depend upon the choice and
concentration of the other ingredients. Preferably, the plasticizer
concentration should be balanced so the vehicle has freeze-thaw
stability, i.e., does not separate after repeated cycles of
solidification (by cooling) and liquefaction (by heating).
The vehicle of this invention can also contain a compatible,
pharmaceutically acceptable coupling agent, the term compatible
having the above-defined meaning. Suitable coupling agents include
saturated fatty acids, fatty amides, and fatty acid esters
discussed hereinbefore under suitable surfactants for creams.
The penetrants increase the penetration and therapeutic activity of
the medicants and are usually solvents or cosolvents for the
medicants. The penetrants can be used in concentrations which are
pharmaceutically acceptable for the intended use not to exceed 20
percent of the weight of the vehicle. Representative examples of
penetrants include dimethylsulfoxide, dimethylacetanide,
dimethylformamide, and the like.
It should be understood that the medicant vehicles of this
invention can also contain non-essential ingredients as discussed
hereinbefore under the section entitled creams.
The vehicle base of U.S. Pat. No. 3,592,930 does not contain any
significant quantity of petrolatum or mineral oil. It is therefore
not a classical ointment and is not water-insoluble. It is
preferably anhydrous, but can contain minor amounts of water such
as up to 3 percent water. The water concentration should not be
sufficient to cause separation of the other vehicle components or
precipitant medicants dissolved in the vehicle.
The vehicles of this invention can be made from the above
ingredients by thoroughly mixing them at ambient or elevated
temperatures. Preferably, the active ingredients are first
dissolved in the glycol solvent, the components are thoroughly
mixed while each is in a liquid state, and the mixture is cooled
with good agitation to room temperature. Good agitation is provided
until the mixture cools to room temperature.
If desired, additional mechanical agitation and/or shock cooling
steps can be used as intermediate or final steps in the
manufacturing process to impart more homogeneity or improve
texture. Processing equipment suitable for these steps is known and
includes heat exchangers, propeller mixers, colloid mills,
homogenizers, roller mills, and the like.
3. Lotion
The corticosteroid mixtures of this invention may also be applied
as a lotion which is a liquid suspension or dispersion of the
active ingredient in water. Generally, along with a glycol/water
mixture the lotion will also employ surfactants and fatty acid
esters such as those set forth above in the discussion of a cream
formulation, along with stabilizers such as an antioxidant and
other adjuvants to improve the aesthetics of the lotion.
A particularly suitable glycol/water solvent mixture will be about
15 to 60%w glycol, preferably the glycol is propylene glycol
present at a level of no more than 45%w of the mixture. The
remainder of the glycol/water mixture will be water, i.e. 40 to
85%w and preferably at least 55%w will be water. A typical
formulation of an acceptable lotion base which is usable in the
application of the steroid mixtures of this invention is given as
follows:
Lotion Base Operative Preferred Ingredient range(%w) range(%w)
______________________________________ Glycol/water solvent 69.5 -
99.8 94.8 - 99.0 Surfactant 0.10 - 10 0.5 - 2.0 Fatty esters 0.10 -
10 0.5 - 2.0 Stabilizer 0 - 10 0.001 - 1 Active ingredients 0.001 -
0.5 0.005 - 0.20 ______________________________________
4. Gel
The corticosteroid mixtures of this invention may also be applied
topically as a gel, that is, a solution of the drug in a colloidal
gel. Typical gelling agents used to prepare pharmaceutically
acceptable gels include bentonite, cellulose derivatives such as
methyl cellulose and carboxymethyl cellulose, tragacanth, gelatin
and, preferably, carboxypolymethylene, e.g. CARBOPOL. The
glycol/water mixture is preferably propylene glycol/water with
about 20%w glycol to about 90%w glycol, and is even more preferably
at least about 60%w glycol. The following is a representative
formulation of the gel formulations of this invention:
Gel Base Operable Preferred Ingredient range(%w) range(%w)
______________________________________ Glycol/water mixture 90 -
99.9 98 - 99.50 Gelling Agent 0.1 - 10 0.5 - 2.0 Active ingredients
0.001 - 0.50 0.010 - 0.20
______________________________________
The cream, ointment, lotion, and gel formulations discussed above
may be modified to include a therapeutically effective amount of an
antibiotic such s penicillin, tetracycline, oxytetracycline,
neomycin, gramicidin, chlorotetracycline, erythromycin, and other
antibiotics known in the art, or mixtures thereof. An effective
amount is whatever amount is needed to effectively reduce bacterial
or fungal infections which may accompany an inflamed condition
which is being treated using the corticosteroid mixture of this
invention. This generally is about 0.1 to 1.0%w of the final
formulation, preferably about 0.2 to about 0.5%w.
Thus, it may be seen that another aspect of this invention is an
improved process of treating an inflammatory condition in animals,
particularly human beings, which process comprises administering a
therapeutically effective amount of an appropriate composition of
this invention as described hereinbefore and those set forth in the
composition claims.
Still another aspect of this invention comprises a process for
preparing the unique compositions of this invention. This process
comprises
a. dissolving at least two corticosteroids chosen from the group
represented by formulas (A) through (K) in a suitable
pharmaceutical solvent so that each corticosteroid is present in
solution at the saturation solubility for each corticosteroid
and
b. mixing said solution from (a) with an effective amount of
suitable pharmaceutical formulation additives to form a topical
pharmaceutical formulation which comprises about 0.001 to about
0.5%w of said corticosteroids.
An effective amount of suitable formulation additives is whatever
amount is needed to form the type of formulation desired such as a
cream, ointment, lotion, gel, and the like. This amount may vary
from about 0.1 to about 99%w of the final formulation, while the
solvent may vary from about 1%w of the formulation to about 99.9%w
of the final formulation.
Generally, the corticosteroids will be dissolved in the solvent at
elevated temperatures, e.g. 40.degree.C to 90.degree.C, then the
formulation additives are mixed together at elevated temperatures
such as 40.degree.C to 90.degree.C. After these individual
components are prepared, they are then comixed thoroughly at
elevated temperatures, again about 40.degree.C to 90.degree.C and
cooled to ambient temperatures with constant agitation.
The following Examples are presented to further show specific,
representative pharmaceutical formulations which are part of this
invention and to distinguish the multisteroid compositions of this
invention over those single-steroid compositions known in the art.
The formulations are presented showing the % weight of each of the
components, including the compounds. The relative amounts of each
compound with reference to compound A as 1.00 are not given in the
examples, but each compound is present in relative amounts as set
forth hereinbefore. The examples are presented as illustrative only
and are not to be construed in a limiting manner.
EXAMPLE 1:
Gel Formulations
An experiment was run to determine the in vitro skin penetration of
gel composition of this invention which is representative of the
gel base formulation discussed hereinbefore. The composition of
this invention included compounds A,C, and D at 0.012, 0.0056 and
0.0045%w, respectively, making a total steroid concentration of
0.0221%w. The penetration of the mixture was compared to the same
total concentration, that is, 0.0221%w of each of the individual
components. The results show that at all sampling times the mixture
gave a greater total drug penetration than did any of the
individual components alone. The results are presented in Table
1.
______________________________________ The following formulations
were prepared I (Composition of the Invention) compound A 0.012 %w
compound C 0.0056 compound D 0.0045 CARBOPOL 0.50 70%w PG/30%w
water qs. ad. 100.00 II (Prior Art Composition) compound A 0.0221
%w CARBOPOL 0.50 70%w PG/30%w H.sub.2 O qs. ad. 100.00 III (Prior
Art Composition) compound C 0.0221 %w CARBOPOL 0.50 70% PG/30%
H.sub.2 O qs. ad. 100.00 IV (Prior Art Composition) compound D
0.0221 %w CARBOPOL 0.50 70% PG/30% H.sub.2 O qs. ad. 100.00
______________________________________
The in vitro penetration of each of the compositions I-IV through
whole thickness human skin was determined by the method described
by Coldman, et al, J. Pharm. Sci., 58, 1098 (1969). The results are
set forth in TABLE I and shown clearly that the total penetration
of a composition of this invention (mixture I) is greater than any
of the prior art compositions at equivalent concentrations.
TABLE I
__________________________________________________________________________
In Vitro Skin Penetration Composition Total Penetration (ng) at
hours 65.5 113.5 161.5 233.5 268 318.1 370
__________________________________________________________________________
I (Invention) 48.3 236 749 1931 2411 2912 3465 II (Art) 40.2 134
401 939 1156 1357 1700 III (Art) 24.6 115 293 629 766 911 1056 IV
(Art) 11.4 52.6 207 608 758 913 1054
__________________________________________________________________________
Similar results may be obtained employing the following
representative gel compositions of this invention.
______________________________________ Composition V compound A
.00565 %w compound C .00264 compound D .0017 CARBOPOL 0.50 60%w
PG/40%w Water qs. ad. 100.00 Composition VI compound A 0.0290 %w
compound C 0.0134 compound D 0.0108 CARBOPOL 0.50 80%w PG/20%w
Water qs. ad. 100.00 Composition VII compound C 0.0134 %w compound
D 0.0108 compound F 0.018 CARBOPOL 0.50 80%w PG/20%w Water qs. ad.
100.00 ______________________________________
Other mixtures of corticosteroids A through K, particularly A, C,
D, E and F, may be prepared with similar results.
EXAMPLE 2
Cream Base Formulations
A particularly valuable cream base formulation representative of
those discussed hereinbefore is given as follows:
Cream Base A ______________________________________ Stearyl Alcohol
15.0 g. Span 60 2.0 g. Tween 60 2.0 g. Mineral Oil 3.0 g. Citric
Acid 0.01 g. PG/Water 77.99 g.
______________________________________
The proportion of water in the PG/water mixture may be varied from
about 85%w or more to less than 10%w, but preferably will be about
80 to about 40%w water (thus the PG/water mixture will be about 15
to 90%w PG, preferably about 20 to 60%w PG).
______________________________________ Composition X compound A
3.52 mg. compound C 2.11 mg. compound E 6.64 mg. cream base A (with
PG/water mixture 60%w PG/40%w water) qs. ad. 100.00 g. Composition
XI compound A .288 mg. compound C .048 mg. compound D .041 mg.
compound E .091 mg. compound F .037 mg. cream base A (with PG/water
mixture 20%w PG/80%w water) qs. ad. 100.00 g. Composition XII
compound A 3.52 mg. compound C 2.11 mg. compound D 1.42 mg.
compound E 6.64 mg. compound F 1.80 mg. cream base A (with PG/water
mixture 60%w PG/40%w water) qs. ad. 100.00 g.
______________________________________
Compositions VIII through XII will show a greater penetration rate
than any of the corticosteroids alone in the same cream base A at
an equivalent concentration. Other representative cream
formulations may be prepared using compounds A through K. The
procedure for preparing the representative cream base composition
of this invention is as follows:
1. The desired amount of the active ingredients (about 0.001 to
0.5% of the total formulated composition) is dissolved in the
PG/water solution and heated to 65.degree.-70.degree.C.
2. The stearyl alcohol, Span 60, Tween 60, Mineral oil and citric
acid are combined and heated to 65.degree.-70.degree.C.
3. The aqueous phase (1) is added to the oil phase (2) with
moderate stirring and the resulting formulation cooled to
30.degree.-35.degree.C.
The following representative formulations are preferable cream
formulations of this invention and are prepared as described
above:
Composition VIII compound A .288 mg. compound C .048 mg. compound E
.091 mg. cream base A (with PG/water mixture 20%w PG/80%w water)
qs. ad. 100.00 g. Composition IX compound A .800 mg. compound E
.360 mg. compound F .472 mg. cream base A (with PG/water mixture
40%w PG/60%w water qs. ad. 100.00 g.
______________________________________
EXAMPLE 3
Water-washable Ointment Base Formulation
A particularly valuable representative anhydrous, water-washable
ointment base formulation follows:
Ointment Base A ______________________________________ Cetyl
alcohol 1.75 g. Stearyl alcohol 19.25 g. PEG 6000 5.00 g. PG 74.00
g. ______________________________________
The procedure for preparing a composition of this invention is as
follows:
1. The desired amount of each of the corticosteroids is dissolved
in the PG at about 80.degree.-85.degree.C.
2. The cetyl alcohol, stearyl alcohol and PEG 6000 are mixed
thoroughly at 80.degree.-85.degree.C.
3. The PG solution (1) is added to the fatty alcohol/PEG mixture
and mixed at 90.degree.-95.degree.C for 30 minutes, then cooled
slowly to room temperature with good agitation.
The following representative compositions of this invention are
prepared as described above:
Composition XIII ______________________________________ compound C
48.1 mg. compound D 39.0 mg. compound F 101.0 mg. Ointment base A
(qs. ad.) 100.00 g. Composition XIV compound A 103.0 mg. compound C
48.1 mg. compound D 39.0 mg. Ointment base A (qs. ad.) 100.00 g.
______________________________________
Compositions XIII - XIV will show a greater penetration rate than
any of the corticosteroids alone in the same ointment base at an
equivalent concentration. Other mixtures of compounds A through K,
particularly A,C,D,E, or F may similarly be prepared.
EXAMPLE 4
Cream Base Formulation
A particularly valuable cream formulation is set forth below:
composition XV
Composition XV ______________________________________ compound A
0.0082 g. compound C 0.0039 compound D 0.0029 Cetyl Alcohol 4.00
Stearyl Alcohol 4.00 Tween 60 2.00 Span 60 2.00 Mineral Oil (MO 15)
5.75 Propylene Glycol 30.00 Purified Water (qs. ad.) 100.00
______________________________________
Procedure
1. dissolve drugs in propylene glycol with moderate heating
(40.degree.-50.degree.C). Heat to 70.degree.-75.degree.C.
2. combine cetyl alcohol, stearyl alcohol, tween 60, span 60, and
mineral oil and heat to 70.degree.-75.degree.C.
3. add aqueous phase (1) to oil phase (2) with stirring on Lightnin
mixer to form an emulsion and cool to 30.degree.-35.degree.C in
water bath with stirring.
Compositions similar to composition XV may be prepared using
mixtures of 2 to 5, especially 3, of the corticosteroids
represented by formulas A through K, particularly those represented
by formulas A,C,D,E and F. Improved penetration rates will be seen
along with enhanced therapeutic response.
EXAMPLE 5
Classical Ointment Base Formulations
Representative of a classical ointment base formulation
follows:
Composition XVI ______________________________________ compound A
.0112 %w compound C .0042 compound F .0110 Mineral Oil 8.00
Propylene glycol 8.00 Tween 60 2.00 Span 60 2.00 White Petrolatum
qs. ad. 100.00 ______________________________________
Procedure
1. dissolve drugs in PG at 40.degree.-50.degree.C
2. combine Mineral oil, Tween, Span and White petrolatum and heat
to about 50.degree.C.
3. combine 1 with 2 with stirring on a "Lightnin" mixer and cool
slowly to room temperature.
Similarly, other ointment based formulations may be prepared using
mixtures of 2 to 5, preferably 3, compounds A through K, especially
3 member combinations of A,C,D,E, and F.
EXAMPLE 6
CREAM FORMULATION WITH ANTIBIOTICS
The formulations of Examples 1 through 5 may be modified to include
a therapeutically effective amount of an antibiotic such as
penicillin, tetracycline, oxytetracycline, neomycin gramicidin,
chlorotetracycline, erythromycin, and other antibiotics known in
the art. Particularly valuable in this regard are the following
cream base formulations which are prepared in a manner similar to
Example 4.
______________________________________ Composition XVII compound A
0.0082 g. compound C 0.0039 compound D 0.0029 Neomycin base (as
sulfate) 0.3500 Cetyl Alcohol 4.0000 Stearyl Alcohol 4.0000 Tween
60 2.0000 Span 60 2.0000 Mineral Oil (MO15) 5.7500 Propylene glycol
30.0000 Purified water qs. ad. 100.0000 g. Composition XVIII
compound A 0.0082 g. compound C 0.0039 compound D 0.0029 Neomycin
base (as sulfate) 0.2875 Gramicidin 0.0275 Mystatin
12.times.10.sup.6 I.U. Cetyl Alcohol 4.0000 Stearyl Alcohol 4.0000
Tween 60 2.0000 Span 60 2.0000 Mineral Oil 5.7500 Propylene glycol
30.0000 Purified Water qs. ad. 100.0000 g.
______________________________________
Compositions similar to compositions XVII and XVIII may be prepared
using mixtures of 2 to 5, especially 3, of the corticosteroids
represented by formulas A through K, particularly formulas A,C,D,E,
and F.
* * * * *